1-oxy-4-methyl-17-oxyacetyl-1, 3, 5-estratrienes and method



United States Patent Q 1-OXY-4-METHYL-17-OXYACETYL-1,3,5 ESTRATRIENESAND METHOD Robert L. Clarke, Elsmere, N. Y., assignor to Sterling DrugInc., New York, N. Y., a corporation of Delaware No Drawing. ApplicationMarch 2, 1956, Serial No. 568,969

4 Claims. c1. 260-39147 I have invented a new classof steroids, namelyl-hydroxy-4-methyl-l7-hydroxyacetyl 1,3,5 estratriene and estersthereof, and a process for their preparation. These compounds possesshormone and enzyme-inhibitory properties, and they are also useful asintermediates in the preparation of other hormonal substances.

1 hydroxy-4-methyl-l7-hydroxyacetyl-1,3,5-estratriene and esters thereofhave the structural formula (IJHzOR CO wherein R is hydrogen or an acylgroup. The acyl group is derived from lower-alkanoic acids such asformic acid, acetic acid, propionic acid and butyric acid,lower-alkanedicarboxylic acids such as oxalic acid, malonic acid andsuccinic acid, or monocyclic-aromatic-carboxylic acids such as benzoicacid, p-nitrobenzoic acid, 3,5-dinitrobenzoic acid and the like.

The above compounds are prepared by treating21-acetoxy-1,4-pregnadiene-3,20-diol, one of the products of thereaction of progesterone with lead tetraacetate, with a solution ofconcentrated sulfuric acid in acetic anhydride. Rearrangement andaromatization of ring A of the steroid molecule occur. The product ispurified by chromatography to give1-hydroxy-4-methyl-l7-hydroxyacetyl-1,3,5-estratriene diacetate. Thelatter is readily saponified to give1-hydroxy-4-methyl-l7-hydroxyacetyl- 1,3,5-estratriene, which can bereesterified by treatment with an acid halide or an acid anhydride. Thestarting material, 21 acetoxy 1,4 pregnadiene-3,20-diol, is described inthe copending application of Aram Mooradian, Serial No. 253,195, filedOctober 25, 1951, now U. S. Patent 2,745,851.

The structure of the compounds of the invention was assigned on thebasis of chemical analysis, the phenolic character of the compound WhereR is hydrogen, and by analogy with the mechanism of reaction determinedby Woodward and Singh, J. Am. Chem. Soc. 72, 494-500 (1950), for modelbicyclic compounds.

The following examples will further illustrate my invention.

EXAMPLE 1 1 -hydrxy-4-m ethyl-1 7-hydroxyacetyl-1,3,5-estratrienedz'acetate To a solution of 900 mg. of2l-acetoxy-l,4-pregnadiene-3,20-dione in 60 ml. of acetic anhydride wasadded, all at once, a solution of 600 mg. of concentrated sulfuric acidin 18 ml. of acetic anhydride. This mixture was "ice allowed to standfor three hours at room temperature, then poured into 250 ml. of icewater and agitated until the excess acetic anhydride had decomposed. Thesolid material was collected by filtration, air dried, and dissolved in150 ml. of ether. An aqual volume of petroleum ether (Skellysolve A) wasadded, and the solution was poured onto a 2 x 53 cm. column containingg. of -200 mesh silica gel. The adsorbed material was then eluted bymeans of a 1:1 mixture of ether and petroleum ether. The first 1.7liters of eluate contained substantially all of the product, andrecrystallization of the material from 12 ml. of acetone gave 523 mg. of1- hydroxy-4-methyl-17-hydroxyacetyl-l,3;5 estratrienedi acetate, M. P.188.5-1895" C., [a'] =+232 (1.77% in chloroform). Evaporation of thefiltrate from recrystallization to a 3 ml. volume and addition of 3 ml.of petroleum ether (Skellysolve A) gave 129 mg. of additional product,M. P. 187.5l89.5 C.

Analysis.-Calcd. for CzsHazOs: C, 72.79; H, 7.82; ace tate, 20.85.Found: C, 72.95; H, 7.70; acetate, 20.65.

EXAMPLE 2 I -hydroxy-4-methyl-1 7 -hydr0xyacetyl-1 ,3,5 -estratriene Amixture of 200 mg. of1-hydroxy-4-methy1-17-hydroxyacetyl-1,3,5-estratriene diacetate,prepared as described above in Example 1, 250 mg. of potassiumbicarbonate, 20 ml. of methanol and 4.5 ml. of water was heated atreflux for two hours. The methanol was removed, the residue extractedwith ether, and the ether extracts dried and concentrated. The resultingsolid residue was recrystallized once from an acetone-petroleum ether(Skellysolve A) mixture and then once from a benzene-petroleum ether(Skellysolve B) mixture to give 88 mg. of1-hydroxy-4-methyl-17-hydroxyacetyl-1,3,5-estratriene, M. P. 215-218"C., [a] =+269+10 (2.65% in ethanol).

Analysis.Calcd. for C21H2BO3: C, 76.80; H, 8.59. Found: C, 76.70; H,8.46.

EXAMPLE 3 l hydroxy-4-methyl-l7-hydroxyacetyl-1,3,5-estratriene reactswith propionic anhydride, succinic anhydride or benzoyl chloride togive, respectively, l-hydroxy-4-methyl- 17hydroxyacetyl-1,3,5-estratriene dipropionate, l-hydroxy 4 methyl17-hydroxyacetyl-1,3,5-estratriene di- (acid succinate) or1-hydroxy-4-methyl-l7-hydroxyacetyl- 1,3,5-estratriene dibenzoate.

1 hydroxy-4-methyl-l7-hydroxyacetyl-1,3,5-estratriene was tested foranti-accelerator activity by measuring its eifect in counteracting thecardiac acceleration produced by epinephrine (5-10 micrograms per cc.)in the isolated perfused rabbit heart. The compound was active at a doseof 100 micrograms per heart. This indicates that the compound also hasbeen similar to those of veratramine, particularly in lowering the bloodpressure.

1 hydroxy-4-methyl-17-hydroxyacetyl-1,3,5-estratriene diacetate wasadministered orally to mice at a dose of 200 mg./kg. of body weight as a2% suspension in 1% gum tragacanth. After 45 minutes a 100 mg./kg. doseof hexobarbital was administered intraperitoneally. It was found thatthe sleeping time in these mice was increased by 22.5-71.2% as comparedto the sleeping time in mice treated with hexobarbital only. Theseresults indicate that l-hydroxy-4-methyl-17-hydroxyacetyl-l,3,5-estratriene diacetate has central nervous system depressant activity andis useful as a potentiaor for barbiturates.

The compounds of the invention can be prepared for use by formulatingsterile aqueous suspensions, or oil solutions or oil-water emulsions,for oral or parenteral injection, in the same manner in whichconventional steroidal substances are formulated.

This application is a continuation-in-part of my co- I claim: 1. Acompound having the formula $H2OR wherein R is a member of the groupconsisting of hydrogen and acyl groups derived from acids selected fromthe 4 v group consisting of lower-alkanoic acids,lower-alkanedicarboxylic acids and monocyclic aromatic carboxylic acids.

2. 1 hydroxy- 4-methyl-17-hydroxyacetyl-1,3,5-estratriene.

3. 1 hydroxy- 4-methyl-17-hydr0xyacetyl-1,3,5-estratriene diacetate.

4. The process for preparing 1-hydroXy-4-methy1-l7-hydroxyacetyl-l,3,5-estratriene diacetate which comprises reacting2l-acetoxy-1,4-pregnadiene-3,20-diol with a solution of concentratedsulfuric acid in acetic anhydride.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.2,799,691 July 16, 1957 Robert L. Clarke It is hereby certified thaterror appears in the printed specification of the above numbered patentrequiring correction and that the said Let cers Patent should read ascorrected below.

Column 2, line 5, for "equal" read equal line 36, for "=+2;Q1+l08" read=+269-l0 line 54, for "been" read use-s line 66, for "potentiaor" readpotentiator Signed and sealed this 1st day of October 1957.,

Attest: KARL H. AJCLINE ROBERT C WATSON Attesting Officer Comissioner ofPatents

1. A COMPOUND HAVING THE FORMULA